Unsaturated carbinol and process



Patented Dec. 16, 1952 UNSATURATED CARBINOL AND PROCESS OF PREPARING SAME Ronald Major Evans, Ickenham, England, assignor to Glaxo Laboratories Limited, Greenford, England, a British company No Drawing. Application July 31, 1950, Serial No. 176,911. In Great Britain August 18, 1949 10 Claims.

This invention is concerned with improvements in or relating to the preparation of a new unsaturated maiibinol namely 3-methyl-1-(1'hydroxy- 2 :6 :6-trimethylcyclohexyl) octa-4 G-dien-l -yn- 3-01 which may be represented by the following structural, formula CH: CH:

therefore there is provided a process for the preparation of a new unsaturated carbinol namely 3-methyl-1- (1 '-hydroxy-2' :6 :6 -trimethylcyclohexyl)octa-4z6-dien-1-yn-3-ol in which a halogeno magnesium derivative of the general formula H OH 2 H OMgX CEGCCH=CHOH= H H- C=CMgX n 33H: 3 13H: H H H H and which is useful in the synthesis of vitamin 15 (where X is chlorine, bromine or iodine) is re- A and related compounds. acted with crotonylidene acetone in the presence It has been found that the new carbinol, can of an inert solvent as herein defined and the ree b t y be p p by reacting a h logen'o sulting organo magnesium complex decomposed magnesium derivative of 2:6:6-trimethyl-1-ethto yield the desired carbinol. ynylcyclohexan-l-ol with crotonylidene acetone The term inert solven as used herein means in the-presence of an inert solvent and subsean organic solvent which has no demonstratable quently" decomposing the resulting complex action on the reactants or the products of the reformed; although it is not desired to limit the action, other than the normal action of solvents invention by any theoretical considerations it is in Grignard reactions. It is preferable to use believed that this reaction may be represented aliphatic ethers and cyclic aliphatic ethers havas follows: ing from 4-10 carbon atoms, for example, diethyl ether, di-n-butyl ether, dioxan and tetrahydro- H OMgX furan; other inert solvents such as benzene or anisole may be used alone or in conjunction with these solvents. It is also preferable that the H solvent used should be as dry as possible. The first stage of the process, namely the reaction of the halogeno magnesium derivative (1B8 with the ketone, is preferably carried out at temperatures within the range of from 20 to +60 C. for several hours, preferably in an inert atmosphere, for example in an atmosphere of H OH CH: .;-,CH; nitrogen. It is also generally desirable to have present a small quantity of an anti-oxidant, e. g. hydroqumone or a-tocopherol. 11 0H 40 The second stage of the process namely the H CH; decomposition of the organo-magnesium com- H/\H plex may be carried out by conventional methods, Accordingly th invention comprises the new example by the use of Water which may P carbinol '3-methyl 1-(1'-hydroxy 2':6':6"-trii othe? reagents E of strongly acldlc methylcyclohexyl) repm; reagents in the decomposition should preferably sented by the following formula be ayoided. It is preferable to use an aqueous solut1on of ammonium chloride for the decompo- C CH CH sition which may, for example be effected at or 0H 5 3 slightly below room temperature. The halogeno magnesium derivative of 2:6:6- H H OH trimethyl-l-ethynylcyclohexan-l-ol may be prepared by conventional methods; it is preferable, H 0H3 according to a further feature of the invention H H g to prepare this derivative by w ting 2:626- According to a further feature of the invention trimethyl-l-ethynylcyclohexan 1 01 with ap proximately 2 mols of an alkyl Grignard reagent, for exampl ethyl magnesium bromide, preferably at a temperature within the range of from -60 C. This reaction is also preferably efiecte'd in an inert atmosphere and in the same solvent as is used for the first stage of the process ac,- cording to the invention.

The new carbinol in the purest form it has been possible to prepare has the following characteristics 2 Boiling point, 100110/l0* mm. Refractive index (1)5"), 1.5240 Light absorption (Ii-hexane):

Max. 2300 A Eitm. 929 6 27,000

EXANIPLE 1 3-methyl-1- (1 'h'ydroa:y-2' :6 :6'- trimethylcyclohemyl) octa-4: 6-dien-1-yn-3-ol 2:6 6etrimethylethynylcyclohexan-l-ol (10 g.) indry ether (24 cc.) was added dropwise to a cooled solution (0-5") of ethyl magnesium bromide (prepared from 3.0 ghof magnesium in .150 cc. dry ether) containing a trace of hydroquinone over a period of '30 minutes. A gum was formed which adhered to the sides of the flask; refluxing for 30 minutes with rapid stirring caused fine dispersion of the gum and on cooling'to 0 the Grignard complex separated as a fine grey powder. Crotonylidene acetone (6.6 .g.) in dry ether (25 c. c.) was added gradually to the stirred Grignard reagent at 0 over a period of 1 hour. After stirring for a further period of 2 hours, during which .time the temperature of the .re-' actants wasallowed to rise to room temperature, the complex was decomposed 'by the addition of ammonium chloride solution (20%,; 250 cc. the product was extracted with ether, the ethereal extract washed with saturated sodium bicarbonate solution and dried over anhydrous potassium carbonate.

Removal of the solvent and distillation of the product gave 3-.methy1-1-'(1'-hydroxy 2':6:-6'- trimethylcyclohexyl).octa-4 :B-dien 1 yn .3 01 (5.25 g. 32%) as a viscous yellow liquid-- 13. P. '100/10 mm., 11. 1.5272. Found C, 78.3; H, 10.5 C1sH2aO2 requires C, 78.2; H, 10.2%.

Light absorption: Maxima 2300 and 2730 A Ei'fg' 887 and 199 a 24,400 and 5,300 respectively.

Active hydrogemzerewitinofi).The glycol '(111 mg.) evolved 202 cc. of methane at '21'/757 mm. equivalent to 2.1 atoms of hydrogen per molecule.

Unsr'zt umtion-The glycol (31.8 mg.) .on hydrogenation in'ethyl acetate using a platinic oxide catalyst absorbed 8.6 cc. of hydrogen at 23/759 mm. equivalent to 3.8 per molecule.

EXAMPLE 2 2:6:6 trimethyl-l-ethynylcyclohexan-l-ol (20 g.; 1 mol) in dry ethyl ether (50 c. c.) was added to a refluxing solution of ethyl magnesium bromide (2.4 mols) {prepared from-7.2g. magnesium and 33.2 g. ethyl bromide in 400 c. e". of. dry ethyl ether) with stirring over a period of 45 minutes. Stirring and refluxing was continued for a further hour, and the mixture then cooled to 20. Crotonylidene acetone (19.9 g.; 1.5 mols) in dry ethyl ether (50 c. c.) was added to the solution with stirring during 1 hour. After stirring at 20 for a further2 hours the mixture was cooled to 10",. and 20% ammonium chloride solution (500 EXAMPLE 3 2:6:6 trimethyl-l-ethynylcyclohexan-l-ol (10 g.) in dry n-butyl ether cc.) was added dropwise to a stirred solution of methyl magnesium iodide (prepared from 3.0 g. of magnesium and 21.6 g. of methyl iodide in 150 c. c. of dry n-butyl ether) over a period of minutes. The solution was warmed at for one hour, cooled to -15 and a solution of crotonylidene acetone (6.7 g.) in dry n-butyl ether c. c.) was added to the rapidly stirred solution over a period .of .one hour. After stirring for a further period of one hour at 10 (during which time .a solid separated from the solution), the reaction mixture was allowed to warm up to room temperature. The complex was decomposed by the additionof N-ammonium hydroxide solution c. .c.), a small amount of a-tocopherol added as an antioxidant, the solution filtered and the ethereal layer separated and dried over anhydrous magnesium sulphate. Removal of the solvent and distillation of the residue gave pure 3-methyl-1- (2' :6 :6 trimethyl-l -hydroxycyclohex yl) octa- 4z6-dien- 1 -yn-3-ol, (3.5 g.; 21%), B. P. 1l0/10- mm. n 1.5240 Light absorption (nhexane) maximum 2290 A,

EXAMPLE 4 2 6 6-trimethyl-l-ethynylcyclohexan-l-ol (10 g.) in dry dioxan (50 c. c. )was added dropwise to a solution of ethyl magnesium chloride (formed from 3 g. magnesium in dry ethyl ether 100 c. c.) over a period of 15 minutes during which time the Grignard complex separated as white solid. The stirred suspension was refluxed .for one hour, the reaction .mixture was .cooled to 0 and crotonylidene acetone (6.7 g.) in dry dioxan magnesium sulphate. Removal of the solvent and distillation of the product gave crude 3-methyl-1- (2' 6' 6' trimethyl-l'-hydroxycyclohexyl) octa-- 1 4:6-dien-1yn-3-o1, B. P. l-110/10 mm. g.; 17%) 11 1.5190. Light absorption (n-hexane) maximum 2290 A l'tm. 310 e 8,500.

EXAIVHPLE 5 to room temperature when a small amount of the Grignard. complex separated as a fine crystalline solid. Crotonylidene acetone (7.0 g.) in tetrahydrofuran (50 c. c.) was added dropwise over a period of one hour and stirring continued for a further period of two hours, the solution remaining homogeneous throughout the reaction. The complex was then decomposed by the addition of water (50 c. 0.) followed by saturated ammonium chloride solution (100 c. c.) a small amount of a-tocopherol added as antioxidant, the ethereal layer separated and dried over anhydrous sodium sulphate. Distillation of the product gave S-methyl-l-(Z:6:6-trimethyl- 1' hydroxycyclohexyDocta 4:6-dien-1-yn-3-o1 (7.0 g.; 42%) B. P. 100110/l0" mm. 12 1.5340.-

Light absorption (n-hexane) maximum 2290 A EXAMPLE 6 2:6:6 trimethyl-l-ethynylcyclohexan-l-ol (20 g.) in dry ether (50 c. c.) was added dropwise to a stirred refluxing solution of ethyl magnesium bromide (prepared from 7.2 g. of magnesium and 33.2 g. of ethyl bromide in 400 c. c. of dry ether) over a period of 45 minutes. The refluxing mixture was stirred for one hour, crotonylidene acetone (13.2 g.) in dry ether c. c.) added over a period of one hour, and reflux continued for a further period of two hours. After cooling to 0 the complex was decomposed by the addition of saturated ammonium chloride solution (500 c. c.) (the temperature not allowed to exceed 20), a small amount of a-tocopherol added as antioxidant and the ethereal layer separated. The solvent was removed under reduced pressure at less than 35 and distillation of the residue gave crude 3-methyl-l-(2:6:6-

trimethyl-l-hydroxycyclohexyl)octa 4:6-dien- 1-yn-3-ol B. P. 1O0--110"/1()- mm. 12.0 g. (36%) 1. As a new compound, 3-methyl-1-(l'-hydroxy 2:6:6' trimethylcyclohexyl)octa 4:6- dien-l-yn-B-ol represented by the following structural formula 2. A process for the preparation of B-methyll-(l hydroxy 2':6:6' -trimethy1cyclohexyl)- octa 4:6-dien-1-yn-3-ol which comprises first reacting a halogeno magnesium derivative of the general formula where X is selected from the group consisting of chlorine, bromine and iodine with crotonylidene acetone in the presence of an inert solvent selected from the group consisting of aliphatic and cyclic aliphatic ethers having from 4-10 carbon atoms at a temperature within the range of from -20 to +60 C. and then decomposing the resulting organo magnesium complex with water to yield the desired carbinol.

3. A process as claimed in claim 2 in which the inert solvent is diethyl ether.

4. A process as claimed in claim 2 in which the inert solvent is di-n-butyl ether.

5. A process as claimed in claim 2 in which the inert solvent is diox-an.

6. A process as claimed in claim 2 in which the inert solvent is tetrahydrofuran.

7. A process as claimed in claim 2 in which the reaction is carried out in an inert atmosphere and in the presence of an anti-oxidant.

3.. A process for the preparation of a 3-methyl- 1 -(1-hydroxy 2' :6 :6 trimethylcyclohexyl) octa-4:6-dien-l-yn-3-ol which comprises first reacting 2 6 6-trimethyl-1-ethynylcyclohexan-1-ol with approximately 2 mols of an alkyl Grignard reagent in an inert solvent selected from the group consisting of aliphatic and cyclic aliphatic ethers containing from 4-10 carbon atoms then reacting the product with crotonylidene acetone in the presence of said inert organic solvent and at a temperature within the range of from 20 to +-60 C. and then decomposing the resulting organo magnesium complex with aqueous ammonium chloride to yield the desired carbinol.

9. A process as claimed in claim 8 in which the said alkyl Grignard reagent is ethyl magnesium bromide.

10. A process as claimed in claim 8 in which the reaction of 2:6:6-trimethyl-1-ethynylcyclohexan-l-ol with the alkyl Grignard reagent is carried out at a temperature of from 0-60 C. in an inert atmosphere.

RONALD MAJOR. EVANS.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS OTHER REFERENCES Milas et al., Jour. Amer. Chem. Soc., vol. 70, pp. 1829-34 (May 1948) (6 pp.)

Heilbron et al., J. Chem. Soc.

(England) August 1949, pp. 2023-27. 

1. AS A NEW COMPOUND, 3-METHYL-1-(1''-HYDROXY - 2'':6:6'' - TRIMETHYLCYCLOHEXYL)OCTA - 4:6DIUEN-1-YN-3-OL REPRESENTED BY THE FOLLOWING STRUCTURAL FORMULA 